Westernization of diet has resulted in the increase of patients suffering from lifestyle-related diseases such as diabetes, hyperlipidemia, and hypertension. Some of these diseases finally lead to arteriosclerotic diseases such as myocardial infarction, angina pectoris, and cerebral infarction and sometimes results in death. As treatment of arteriosclerotic diseases, for example, drugs or surgical methods such as vascular angioplasty are generally utilized.
For prevention of arteriosclerotic diseases or improvement of quality of life, it is important to reduce risk factors such as hyperlipidemia, diabetes, hypertension, and smoking habits. In the major epidemiological survey where incidence rates of hyperlipidemia and coronary artery disease were examined, positive correlation was found between serum total cholesterol (hereinafter abbreviated as T-Cho) concentration or serum triglyceride (hereinafter abbreviated as TG) concentration and the onset of the coronary artery disease. More specifically, even stronger positive correlation was found for the serum low density lipoprotein cholesterol (hereinafter abbreviated as LDL-Cho) concentration, while negative correlation was found for the serum high density lipoprotein cholesterol (hereinafter abbreviated as HDL-Cho) concentration.
Pharmacotherapy of hyperlipidemia has become relatively easy, and suppression of onset of coronary artery diseases by a strong therapy of hyperlipidemia using 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (hereinafter abbreviated as HMG-CoA RI) has been proven in a large scale clinical trial. For example, when male hyperlipidemia patients with no history of myocardial infarction were orally administered with pravastatin sodium for an average period of 4.9 years, serum T-Cho concentration decreased by 20%, serum LDL-Cho concentration decreased by 26%, serum HDL-Cho concentration increased by 5%, and serum TG decreased by 12%, and as a consequence, the total incidence rate of nonfatal myocardial infarction and cardiovascular death decreased by 31% (The New England Journal of the Medicine, 1995, vol. 333, pp. 1301-1307). When patients with history of angina pectoris or myocardial infarction were orally administered with simvastatin for an average period of 5.4 years, serum T-Cho concentration decreased by 25%, and serum LDL-Cho concentration decreased by 35%, serum HDL-Cho concentration increased by 8%, and serum TG decreased by 10%, and as a consequence, the incidence rate of major cardiovascular events decreased by 34% (The Lancet, 1994, vol. 344, the issue of, pp. 1383-1389). The decrease in the incidence rate of the cardiovascular events was also approximately 20 to 30% in other large scale clinical trials using HMG-CoA RI (Archives of Internal Medicine, 1999, vol. 159, No. 1, pp. 1793-1802). These results may not be sufficient for clinical practice.
It has been reported that when a capsule that includes a ω-3 polyunsaturated fatty acid composition containing EPA-E and ethyl docosahexaenoate (hereinafter abbreviated as DHA-E) in a total amount of 850 to 882 mg was orally administered to patients within three months from the onset of acute myocardial infarction every day for 3.5 years, the combined incidence rate of cardiovascular death, nonfatal myocardial infarction, and nonfatal cerebral infarction decreased by 20%, and that, while cardiovascular death decreased by 30%, no significant effect was observed on nonfatal cardiovascular events (The Lancet, vol. 354, Aug. 7, 1999, pp. 447-455). It was also reported that their death rate decreased when 1 g of essential fatty acids containing EPA-E and DHA-E in a total amount of 85% was administered to patients with history of myocardial infarction every day for 3.5 years (WO00/48592 (JP 2002-537252 A)). It is also disclosed that the use of EPA or DHA in combination with a cholesterol synthesis inhibitor represses cardiovascular events (U.S. Pat. No. 6,159,993).
High purity EPA-E is commercially available in the trade names of Epadel and Epadel S (manufactured by Mochida Pharmaceutical Co., Ltd.) as the therapeutic drug for hyperlipidemia. It has been reported that when such high purity EPA-E is orally administered at 600 mg per administration and three times a day immediately after meals (when serum TG is abnormal, the dose can be increased to the level of 900 mg per administration and three times a day), serum T-Cho concentration and serum TG can be reduced by 3 to 6% and by 14 to 20%, respectively (Drug Interview Form “EPA preparation, Epadel capsule 300”, revised in July, 2002; January, 2003; pp. 21-22.), and that, based on such action, such high purity EPA-E is expected to exert effects on cardiovascular events of hyperlipidemia patients (American Heart Journal, 2003, vol. 146, No. 4, pp. 613-620.).
On the other hand, as an option for treatment of Ischemic heart disease, a surgical treatment, cardiovascular angioplasty such as PTCA, and coronary stent implantation has been widely carried out mainly for serious patients, but cardiovascular events are easy to occur after the angioplasty. For example, the cardiovascular event after PTCA is due to restenosis at the PTCA site, which generally means progression of stenosis in more than 50% of the region expanded by PTCA, or generation of new lesion in many cases. The restenosis rate is approximately 30-40% and the restenosis is usually observed at or within six months. The restenosis rate can be reduced by using a stent but it is not always reliable (T. Yamaguchi & M. Kitahara, Kon-nichi no tiryoushishin, published by IGAKUSHOIN, pp. 237, 2003).
As medical treatment with drugs after cardiovascular angioplasty, anti-platelet agents are often used. For example, a combination of aspirin and Ticlopidine (Clopidogrel) is administered as a matter of course when a stent is inserted. For prevention of stent thrombi, a combination of aspirin and cilostazol is administered (T. Yamaguchi & M. Kitahara, Kon-nichi no tiryoushishin, published by IGAKUSHOIN, pp. 245-246, 2003). In particular, care after the surgery is considered important.
Although fish oil or ornega-3 fatty acids have been administered to the patients with restenosis in the unstable period after cardiovascular angioplasty, there are controversial reports regarding their efficacy, while there is a view that they have to start to be administered before the cardiovascular angioplasty (J Am Coll Cardiol. 2005 May 17;45(10):1723-8; Am Heart J. 2002 June; 143(6):E5; J Am Coll Cardiol. 1999 May; 33(6):1619-26; Am J Cardiol 77,31-36 (1996)).
Although it was reported that two-year administration of HMG-CoA RI, plavastatin, after PTCA had reduced the restenosis rate and thus been effective for repression of the cardiovascular events (Am J Cardiol. 2000 Oct. 1;86(7):742-6) as well as that three- to four-year administration of fluvastatin from immediately after Percutaneous Coronary Artery intervention repressed the onset of the the cardiovascular events (JAMA. 2002 Jun. 26;287(24):3215-22), an improved treatment is expected, which enable more repression of the cardiovascular events.